Structure, Expression, and Function of Atrial Natriuretic Factor in Extraatrial Tissues*

Gutkowska, Jolanta; Nemer, Mona

doi:10.1210/edrv-10-4-519

Cited by 185 publications

(84 citation statements)

References 88 publications

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Section: Discussionmentioning

confidence: 99%

“…It is known that ANF and ANF receptors are expressed in oral epithelial cells (13,14,49). Indeed, it has actually been suggested for over a decade that ANF might have noncardiovascular autocrine and paracrine functions (13). Epithelial ANF may have a physiological role in the regulation of fluid secretion of the lacrimal and submaxillary glands and ducts analogous to its cardiovascular fluid homeostasis role (15,50,51).…”

Section: Discussionmentioning

confidence: 99%

“…However, although ANF was first identified as a hormone produced in the cardiac atrium, it is also expressed in extra-atrial tissue, suggesting that ANF might have autocrine and paracrine functions outside the cardiovascular system (13). Most notably, ANF has been found in epithelial cells of the kidney, adrenal, pancreas, salivary, and lacrimal glands (13)(14)(15).…”

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confidence: 99%

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Cell-specific Activation of the Atrial Natriuretic Factor Promoter by PITX2 and MEF2A

Toro¹,

Saadi²,

Kuburas

et al. 2004

Journal of Biological Chemistry

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The PITX2 homeodomain protein is mutated in patients with Axenfeld-Rieger syndrome and is involved in the development of multiple organ systems, including the heart. We have examined the interaction of PITX2 isoforms with myocyte-enhancing factor 2A (MEF2A), which is a known regulator of cardiac development. A direct interaction between PITX2a and MEF2A was demonstrated using yeast two-hybrid and GST pulldown assays. To study the functional significance of this interaction, we used the atrial natriuretic factor (ANF) promoter. Coexpression of MEF2A and PITX2a or Pitx2c resulted in a strong synergistic activation of the ANF promoter in LS8 oral epithelial cells but not in other cell lines (NIH/3T3, Chinese hamster ovary, or C2C12). The synergism was dependent on promoter context, because it required MEF2 binding sites and was not seen with two other PITX2 target promoters. DNA binding by MEF2A was required but not sufficient for synergism. Upstream activators of p38 MAP kinases, MKK3 and MKK6, increased PITX2a and Pitx2c activity to yield up to 90-fold activation of the ANF promoter in LS8 cells. Because Axenfeld-Rieger syndrome is autosomal dominant and affects development of the oral epithelium, we tested one of the known PITX2 mutants. The PITX2a-K88E mutant protein suppressed wild type PITX2a synergism with MEF2A. These results demonstrate a promoter-and cell-specific functional interaction between PITX2 and MEF2A and suggest the possibility of coordinate control by these factors in the oral epithelium.The PITX2 gene was cloned based on its linkage in AxenfeldRieger syndrome (ARS) 1 (1). ARS is an autosomal dominant human disorder characterized by ocular anterior chamber anomalies causing glaucoma in Ͼ50% of affected individuals as well as dental hypoplasia, mild craniofacial dysmorphism, and umbilical stump abnormalities (1-3). Other features associated with this syndrome include abnormal cardiac, limb, and pituitary development. PITX2 is a member of the bicoid/paired-like homeodomain family (3, 4). There are three isoforms, PITX2a, b, c, that differ only in their amino-terminal regions. The Pitx2 knock-out mouse is lethal at embryonic day 15 because of cardiac abnormalities and shows defects in cardiac positioning, atrial septation, and outflow tract development (4). Pitx2 is a proliferation target in the Wnt/Dvl pathway, which, when disrupted, leads to cardiac outflow tract abnormalities (5). Pitx2 has also been shown to be a downstream target in left-right asymmetry pathways and organogenesis (6 -9). It is expressed asymmetrically on the left side of the lateral plate mesoderm and derivative organs, including the heart and the gut.We have used the yeast two-hybrid assay to analyze candidate PITX2 interacting partners. With respect to the role of PITX2 in heart development, we were intrigued by the recent findings that PITX2 could activate the promoter of the atrial natriuretic factor (ANF) gene (10). ANF plays a key role in electrolyte and fluid homeostasis in the cardiovascular system by causing natriure...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Cell-specific Activation of the Atrial Natriuretic Factor Promoter by PITX2 and MEF2A

Toro¹,

Saadi²,

Kuburas

et al. 2004

Journal of Biological Chemistry

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“…The guanylate cyclasecoupled receptors (NPR-A) are signaling receptors that mediate all known cardiovascular and renal effects of ANP via cGMP (2,4). The functions of the natriuretic peptides, however, are not restricted to the regulation of volume homeostasis as suggested earlier by demonstration of ANP and its receptors in diverse tissues besides the cardiovascular and renal system (5). ANP was suggested to play a role in the immune system because thymus (6 -8) and macrophages (9,10) are sites of synthesis of the natriuretic peptide and its receptors.…”

Section: Atrial Natriuretic Peptide (Anp)mentioning

confidence: 99%

Autocrine Regulation of Inducible Nitric-oxide Synthase in Macrophages by Atrial Natriuretic Peptide

Kiemer

Vollmar

1998

Journal of Biological Chemistry

105

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Atrial natriuretic peptide (ANP), a cardiovascular hormone, has been shown to inhibit synthesis of nitric oxide in lipopolysaccharide (LPS)-activated mouse bone marrow-derived macrophages via activation of its guanylate cyclase-coupled receptor. The goal of the present study was to elucidate the potential sites of inducible nitric-oxide synthase (iNOS) regulation affected by ANP and revealed the following. 1) ANP and dibutyryl-cGMP did not inhibit catalytic iNOS activity measured by the conversion rate of L-[ H]arginine to L-[ H]citrulline in homogenates of LPS-treated cells. 2) Pretreatment of cells with ANP dose-dependently reduced the LPS-induced L-[3 H]citrulline production that has been shown to be due to reduced iNOS protein levels detected by Western blot. 3) ANP does not alter the ratio of catalytically active iNOS dimer versus inactive iNOS monomer considered to be a major post-translational regulatory mechanism for the enzyme. 4) Macrophages exposed to ANP display decreased LPS-induced iNOS mRNA levels. 5) Importantly, two basic mechanisms seem to be responsible for this observation, i.e. ANP specifically induced acceleration of iNOS mRNA decay and ANP reduced binding activity of NF-B, the transcription factor predominantly responsible for LPS-induced iNOS expression in murine macrophages. Moreover, 6) ANP acts via an autocrine mechanism since recently ANP was shown to be secreted by LPS-activated macrophages, and we demonstrated here that LPS-induced NO synthesis was increased after blocking the binding of endogenous ANP by a receptor antagonist. These observations suggest ANP as a new autocrine macrophage factor regulating NO synthesis both transcriptionally and post-transcriptionally. ANP may help to balance NO production of activated macrophages and thus may allow successful immune response without adverse effects on host cells.

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“…Furthermore, there is increasing evidence that it may play a role in immune and reproductive functions (8,9). ANF circulates as a 28-amino acid C-terminal fragment and a 98-amino acid N-terminal fragment.…”

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confidence: 99%

Role of the liver in splanchnic extraction of atrial natriuretic factor in the rat

et al. 1992

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Mesenteric, hepatic and splanchnic extraction of C-terminal and N-terminal atrial natriuretic factor was investigated in male Sprague-Dawley rats. Plasma concentrations (mean f S.E.M.) of C-terminal atrial natriuretic factor were 55.0 f 6.1 fmouml, 31.2 f 4.0 fmoUml and 23.5 f 3.3 fmol/ml (n = 12) in the abdominal aorta, the portal vein and the hepatic vein, respectively. N-terminal atrial natriuretic factor plasma levels in these vessels were 3031 * 766 fmoUml, 2264 f 661 fmoUml and 1618 f 496 fmol/ml (n = 61, respectively. Although the mesenteric extraction ratio was higher (p < 0.05) for C-terminal atrial natriuretic factor (42% f 6%) than for N-terminal atrial natriuretic factor (28% f 4%), there were no significant differences in the hepatic extraction ratio (41% f 6% vs. 39% f 6%) and the splanchnic extraction ratio (56% k 5% vs. 50% f 7%). These data suggest a major role of the liver in the splanchnic extraction of C-terminal and of N-terminal atrial natriuretic factor in the rat. (HEPA"KOGY 1992;16790-793.)The atrial natriuretic factor (ANF) has been shown to be involved in volume homeostasis (1-7). Furthermore, there is increasing evidence that it may play a role in immune and reproductive functions (8,9). ANF circulates as a 28-amino acid C-terminal fragment and a 98-amino acid N-terminal fragment. Although the C-terminal fragment is known to be the bioactive compound of ANF, the biological role of the N-terminal is not yet clearly established. However, there is evidence of a vasodilatory effect of this fragment after further cleavage in plasma (10). However, these may be questions of considerable interest because there is conflicting information on ANF plasma concentrations in liver disease (7,(15)(16)(17). Therefore, to characterize the extraction of circulating ANF in more detail, we investigated the role of the liver in extraction of C-terminal and N-terminal ANF in rats. MATERIALS AND METHODS Animals.Male Sprague-Dawley rats weighing 280 gm to 330 gm and kept under standardized conditions were anesthetized with sodium pentobarbital intraperitoneally (60 mg/kg), heparinized with 250 IU intravenously and then laparotomized. Multiple blood sampling was carried out by direct vessel puncture (abdominal aorta and portal vein) or by venous catheterization with a 20-gauge Teflon cannula (hepatic vein). Blood was immediately transferred into precooled tubes containing EDTA (1 mg/ml), centrifuged at 1500 gm and stored at -70" C until assay.RIA for ANF. C-terminal ANF (99 to 126) was determined in the extract of 100 ~1 plasma by use of antibody Toni I11 (18, 191, as published previously. Intraassay and interassay variations were below 10% and 15%, respectively; recoveries averaged 70%. The RIA for the N-terminal fragment of pro-ANF was performed with 50 ~1 plasma and antibody GT 23 as described elsewhere in detail (20). The intraassay and interassay coefficients of variation were less than 12%, and recoveries were close to 100%. 80- 60- RESULTSThe plasma concentrations of C-terminal ANF in the hepatic v...

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Structure, Expression, and Function of Atrial Natriuretic Factor in Extraatrial Tissues*

Cited by 185 publications

References 88 publications

Cell-specific Activation of the Atrial Natriuretic Factor Promoter by PITX2 and MEF2A

Cell-specific Activation of the Atrial Natriuretic Factor Promoter by PITX2 and MEF2A

Autocrine Regulation of Inducible Nitric-oxide Synthase in Macrophages by Atrial Natriuretic Peptide

Role of the liver in splanchnic extraction of atrial natriuretic factor in the rat

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